Research Summary

DNA damage occurs frequent in living cells. Breaks at the both strands of the DNA helix - DNA double strand breaks is the most severe form of DNA damage. It can happen during DNA replication, as a result of exposure to metabolic by products (e.g. reactive oxygen species) or environmental insults (e.g. radiation), or as programmed events required for lymphocyte development, specifically V(D)J recombination during the assembly of antigen receptor genes and Class Switch Recombination during B cell maturation. While those programmed DNA double strand break events are essential for the diversity and potency of adapted immune system, mistakes in resolving those programmed DNA double strand breaks often lead to large chromosome rearrangement such as translocation, gene amplification and deletions, which are the hallmarks of lymphoma and leukemia. As a result, human patients with mutations in DNA double strand break response and repair genes are often immune deficient and are predisposed to lymphoid malignancy.

Our lab is interested in understanding how mammalian cells sense DNA double stand breaks, integrate cell cycle progression and cellular survival to facilitate high-fidelity repair and to prevent oncogenic transformation. In particular we are interested in:

1) the functional interaction between ATM kinase and its downstream target proteins with non-homologous end joining pathway;
2) reveal the molecular mechanism of oncogenic translocations using ATM deficient mouse models;
3) how DNA double strand break repair is regulated in different phase of cell cycles;
4) how defects in DNA double stand break repair affect lymphocyte development and development of lymphomas.

In the context, we have developed novel mouse models using gene-targeting, based on conditional inaction of ATM and other repair factors in different stage of developing lymphocytes. A broad range of laboratory approaches ranging from basic molecular genetic, biochemistry, cell biology to cytogenetic are applied to monitor the kinetics of DNA repair and consequence of repair deficiencies - translocations and oncogenic transformation.


Affilations

Institute for Cancer Genetics
Department of Pathology and Cell Biology
Department of Pediatrics

Selected Publications

1. Zha S, Jiang W, Fujiwara Y, Patel H, Goff PH, Brush JW, Dubois RL, Alt FW. Ataxia telangiectasia-mutated protein and DNA-dependent protein kinase have complementary V(D)J recombination functions. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2028-33.

2. Zha S, Guo C, Boboila C, Oksenych V, Cheng H, Zhang Y, Wesemann DR, Yuen G, Patel H, Goff PH, Dubois RL and Alt FW. XLF Has Functional Redundancy with ATM and H2AX in Non-homologous DNA End-joining. Nature 2011 Jan 13;469(7329):250-4.

3. Zha S, Bassing CH, Sanda T, Brush JW, Patel H, Goff PH, Gatti R, Look AT, Alt FW. ATM-Deficient Thymic Lymphoma Is Associated With Aberrant TCRδ Rearrangement And Gene Amplification. J Exp Med. 2010 Jul 5;207(7):1369-80.

4. Zha S, Boboila C, Alt FW. Mre11: roles in DNA repair beyond homologous recombination. Nat Struct Mol Biol. 2009 Aug;16(8):798-800 News and Views

5. Calle E, Jankovic M, Wong N, Zha S, Chen H, Difilippantonio S, Di Virgilio M, Heidkamp G, Alt FW, Nussenzweig A and Nussenzweig M. Essential Role for DNA-PKcs in DNA Double-Strand Break Repair and Apoptosis in ATM Deficient Lymphocytes. Mol Cell. 2009 May 15;34(3):285-97

6. Derudder M, Cadera EJ, Vahl JC, Wang J, Fox CJ, Zha S, van Loo G, Pasparakis M, Schlissel MS, Schmidt-Supprian M, Rajewsky K. Efficient κ-chain editing, but defective generation of λ⁺ B cells in the absence of NF-κB signaling. Nat. Immunology. Nat Immunol. 2009 Jun;10(6):647-54.

7. Li G, Alt FW, Cheng HL, Brush JW, Goff PH, Murphy MM, Franco S, Zhang Y, Zha S. Lymphocyte-Specific Compensation For XLF/Cernunnos End-Joining Functions In V(D)J Recombination. Mol. Cell. 2008 Sept.5;31(5):631-40.

8. Zha S, Sekiguchi J, Brush JW, Bassing CH, Alt FW. Complementary functions of ATM and H2AX in development and suppression of genomic instability. Proc Natl Acad Sci U S A. 2008 Jul 8;105(27):9302-6.

9. Zha S, Alt FW, Cheng HL, Brush JW, Li G. Defective DNA repair and increased genomic instability in Cernunnos-XLF-deficient murine ES cells. Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4518-23.

10. Franco S, Gostissa M, Zha S, Lombard DB, Murphy MM, Zarrin AA, Yan C, Tepsuporn S, Morales JC, Adams MM, Lou Z, Bassing CH, Manis JP, Chen J, Carpenter PB, Alt FW. H2AX prevents DNA breaks from progressing to chromosome breaks and translocations. Mol Cell. 2006 Jan 20;21(2):201-14.

Honors and Awards

2010-2013 St. Baldrick Scholar for Pediatric Oncology
2010-2011 John M. Driscoll, Jr., M.D. Children's Fund Awards
2009 Bristol-Myers Squibb Oncology Award, American Association for Cancer Research
2007-2010 Senior Fellowship Award, Leukemia and Lymphoma Society
2004-2007 Fellowship Award, Leukemia and Lymphoma Society
2006 Young Investigator Award, Ataxia- Telangiectasia Workshop, Banff, Canada
2003 AFLAC Award, American Association for Cancer Research

Keywords

DNA repair, lymphocyte development, cancer and translocation
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